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Good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use

This Directive lays down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use. It repeals Directive 91/356/EEC laying down the principles and guidelines of good manufacturing practice for medicinal products for human use, in order to be able to extend and adapt the provisions of that Directive to cover good manufacturing practice for investigational medicinal products for human use.

ACT

Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use

SUMMARY

Commission Directive 91/356/EEC laid down the principles and guidelines of good manufacturing practice* only for medicinal products* for human use. The majority of the provisions in Directive 91/356/EEC therefore had to be amended, extended and adapted in order to cover good manufacturing practice for investigational* medicinal products for human use. This Directive therefore repeals Directive 91/356/EEC in order to lay down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use.

The principles and guidelines of good manufacturing practice relate mainly to personnel, premises and equipment, production, documentation, quality control and labelling, work contracted out, inspections, complaints and product recalls.

Quality assurance system: personnel, premises and equipment

The manufacturer implements an effective pharmaceutical* quality assurance system, involving the management and personnel of the various departments concerned.

At each manufacturing site, the manufacturer has personnel with the skills to achieve the pharmaceutical quality assurance objective.

The personnel receives regular training covering the theory and application of quality assurance and good manufacturing practice and the requirements for the manufacture of investigational medicinal products.

Hygiene programmes that are adapted to the activities to be carried out must be established. These must include procedures relating to the health, hygiene practice and clothing of personnel.

Premises and manufacturing equipment must also be subject to extremely strict hygiene standards in order to avoid contamination and any adverse effect on the quality of the product.

Moreover, premises and equipment used for manufacturing operations which are critical for the quality of the products must be subjected to appropriate validation.

Production

Production must be carried out in accordance with good manufacturing practice and must follow the pre-established instructions and procedures. Process deviations and product defects must be documented and investigated.

Technical and/or organisational measures must be taken in order to avoid, in particular, cross-contamination. In the case of investigational medicinal products, particular attention must be paid to the handling of products during and after any blinding operation*.

For medicinal products, new manufacturing processes and those that have been substantially changed must be validated, and critical phases of the manufacturing process must be regularly revalidated.

In the case of investigational medicinal products, at least the critical process steps, such as sterilisation, and if necessary the manufacturing process in its entirety must be validated.

Documentation

The manufacturer must set up a system of documentation covering the various manufacturing operations carried out. These documents trace the history of the manufacture of each batch and the changes introduced during the development of an investigational medicinal product.

Electronic or other data processing systems may replace written documents. In this case, the manufacturer must prove that the data will be appropriately stored during the period in question.

Quality control and labelling

The manufacturer must set up a quality control system. This system is placed under the authority of a person who has the requisite qualifications and is independent of production. This person has access to quality control laboratories in order to carry out the necessary examination of the starting materials and packaging materials and the testing of intermediate and finished products. Contract laboratories may be used if authorised.

During the final control of the finished product before its release, the quality control system must take into account the production conditions, the results of in-process controls, the examination of the manufacturing documents and the conformity of the product to its specifications.

Samples of each batch of finished medicinal product must be retained for at least one year after the expiry date. In the case of investigational medicinal products, samples of each batch of bulk formulated product and of key packaging components used for each finished product batch must be retained for at least two years after completion of the last clinical trial in which the batch was used.

In addition, samples of certain raw materials used in the manufacturing process must be retained for at least two years after the release of the product. This period may be shortened in certain cases.

For investigational medicinal products, labelling must be such as to ensure protection of the subject and traceability, facilitate proper use of the investigational medicinal product and allow identification of the product and trial.

Work contracted out

Any manufacturing operation must be the subject of a written contract between the contract giver and the contract acceptor. This contract sets out the responsibilities of each party. The contract acceptor must respect the principles and guidelines of good manufacturing practice and must submit to inspections carried out by the competent authorities.

Complaints, product recall and emergency unblinding*

Member States must set up inspections in order to ensure that manufacturers* respect the principles and guidelines of good manufacturing practice laid down by this Directive. They must also take into account Community procedures on inspections and exchange of information.

The manufacturer must ensure that manufacturing operations are carried out in accordance with good manufacturing practice and with the manufacturing authorisation, including medicinal products intended for export. Regular self-inspections must be conducted in order to monitor compliance with good manufacturing practice and, if necessary, to propose corrective measures.

For the purposes of interpreting the principles and guidelines of good manufacturing practice, the manufacturers and the competent authorities must refer to the guidelines set out in the "Guide to good manufacturing practice (GMP) for medicinal products and for investigational medicinal products" , published by the Commission.

With regard to medicinal products and investigational medicinal products imported from third countries, importers must ensure that their manufacture conforms to standards equivalent to the good manufacturing practice developed by the Community. Moreover, an importer of medicinal products must ensure that the persons manufacturing these are authorised manufacturers, and an importer of investigational medicinal products must ensure that their manufacturer is notified to the competent authorities and accepted by them.

To place a medicinal product on the market in a Member State, a marketing authorisation must be granted by the competent authority of that Member State or by the European Agency for the Evaluation of Medicinal Products. The manufacturer must ensure that medicinal products are manufactured in accordance with the information provided in the application for marketing authorisation as accepted by the competent authorities.

With regard to investigational medicinal products, the manufacturer must ensure that they are manufactured in accordance with the information provided by the sponsor and accepted by the competent authorities.

For both medicinal products and investigational medicinal products, the manufacturer must examine and record complaints regarding a defect. He must inform the competent authority of any defect that could result in a recall or restriction on supply and indicate the country of destination. In the case of investigational medicinal products, he must also indicate the trial sites.

For investigational medicinal products, the sponsor must implement a procedure for the rapid unblinding of blinded products, where this is necessary for a prompt recall. The sponsor must also ensure that the procedure discloses the identity of the blinded product only in so far as is necessary.

Key terms in the Act
  • Good manufacturing practice: the part of quality assurance which ensures that medicinal products are consistently produced and controlled in accordance with the quality standards appropriate to their intended use.
  • Medicinal product: any product as defined in Article 1(2) of Directive 2001/83/EC.
  • Investigational medicinal product: any product as defined in Article 2(d) of Directive 2001/20/EC.
  • Manufacturer: any person engaged in activities for which the authorisation referred to in Article 40(1) and (3) of Directive 2001/83/EC or the authorisation referred to in Article 13(1) of Directive 2001/20/EC is required.
  • Pharmaceutical quality assurance: the total sum of the organised arrangements made with the object of ensuring that medicinal products or investigational medicinal products are of the quality required for their intended use.
  • Blinding: the deliberate disguising of the identity of an investigational medicinal product in accordance with the instructions of the sponsor.
  • Unblinding: the disclosure of the identity of a blinded product.

REFERENCES

ActEntry into forceDeadline for transposition in the Member StatesOfficial Journal
Directive 2003/94/EC20 days after publication in the Official Journal (04.11.2003)30.04.2004OJ L 262, 14.10.2003

RELATED ACTS

Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency [Official Journal L 136, 30.04.2004].

Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use [Official Journal L 136, 30.04.2004].

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use [Official Journal L 311, 28.11.2001].

Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use [Official Journal L 121, 01.05.2001].

Last updated: 05.09.2007

See also

  • Directorate-General for Health and Consumers - Medicinal products for human consumption (EN)
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